The retinal degenerative (RD) diseases are a heterogeneous group of conditions that range from the Mendellian inherited orphan diseases such as retinitis pigmentosa (RP) to the genetically complex disease age-related macular degeneration (AMD). With the exception of the neovascular (wet) form of AMD, these diseases remain essentially untreatable. As one approach to both increase our understanding of these diseases and develop novel treatment strategies, we propose to perform phenotypic screens for small molecules that could serve as molecular probes and/or lead molecules for drug development. In our first aim we propose to conduct high content screens (HCS) for photoreceptor (PR) differentiation-promoting and PR neuroprotective compounds using mouse primary retinal cultures, which have significant advantages over the use of established cell lines. As proof of principle for this approach, we have successfully used this strategy in the past to identify compounds that are neuroprotective for retinal ganglion cells both in vitro and in vivo. I aim 2, we propose a variety of secondary assays to characterize, classify and prioritize the active molecules identified in our primary screens. Another PR biological pathway that is sensitive to perturbation is the clearance of PR outer segments (OS). More than a dozen different mutations in the gene for MER tyrosine kinase (MERTK), which encodes the retinal pigment epithelial (RPE) cell receptor necessary for PR OS phagocytosis, have been shown to cause RP. In aim 3, using an assay based upon human stem cell derived MERTK -mutant RPE cells, we will screen for compounds that can increase MERTK-independent RPE phagocytosis.